Primary Immunodeficiency diseases (PIDs) are a heterogeneous group of genetic disorders of that affect the development and/or function of the immune system. The study of PID has helped decipher the cellular and molecular processes that govern immune function. Identification of the genetic defect in PIDs may have prognostic and therapeutic implications. Because most PIDs are inherited as autosomal recessive traits, genetic studies targeted to large consanguineous families are successful in identifying novel gene defects in patients with PIDs that are still genetically undefined, as has been already the case in several disorders. We have established a research network with PID centers in the Middle East and have collected 26 unrelated consanguineous families. In each case, the phenotype is either entirely novel or has been previously described but the known disease-causing gene(s) are intact in sequence and expression. The goal of the proposed research is to test the power of combining Single Nucleotide Polymorphism microarray (SNP) analysis and whole genome sequencing (WGS) to identify novel genes that cause PIDs. Our specific aims are I. Identify the molecular and cellular bases underlying novel PID phenotypes II. Identify the molecular and cellular bases of PID with known phenotypes, but unknown genotype we anticipate that the combination of SNP analysis, WGS and cutting-edge bioinformatics will provide a rapid and cost effective approach to the discovery of novel PID genes. This will pave the way for widespread application of this technology to the study of PIDs and will generate hypotheses on the pathogenesis of PIDs that can be tested in patients and in animal models. The results obtained will be applicable to sporadic cases of PIDs with similar phenotype and will improve our understanding of the human immune system. PUBLIC HEALTH RELEVANCE: Primary Immunodeficiency diseases (PIDs) are a heterogeneous group of genetic disorders of the immune system. Identification of the genetic defect in PIDs may have prognostic and therapeutic implications. PIDs are more common among populations in areas with a high consanguinity rate, and the study of families from such areas has led to identification of several PID causing genes. We have established a research network with PID centers in the Middle East and have collected 26 unrelated consanguineous families of unknown genetic cause. We propose to use cutting edge genetic analysis tools to identify novel genes that cause PIDs. We anticipate that the knowledge gained from the proposed studies will provide a rapid and cost effective approach to the discovery of novel PID genes and will improve our ability to diagnose patients with PIDs in Western countries, where they often present as isolated cases. The results obtained will also enhance our understanding of the human immune system.